Spontaneous NMDA channel activity has been reported in hippocampal, cortical, and cerebellar slice preparations. The exact source and concentration of the glutamate giving rise to this activity is unknown, as is the location of the receptors. In order to understand the role of NMDA receptors in neuropathies such as epilepsy and excitotoxicty as well as their function in synaptic plasticity and development, it is important to determine the mechanisms of this tonic activation. Specifically: is spontaneous NMDA channel activity associated with spontaneous vesicular release, what role does extrasynaptic glutamate play in this activity, and how long and at what concentration is the glutamate underlying the activity present? To answer these questions, whole cell recordings of pyramidal neurons in transverse hippocampal slices will be taken with the aid of infrared differential interference contrast video microscopy. Using pharmacology and kinetic modeling the specific aims of this proposal will be addressed.